Brinzolamide R-(+)-4ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H thieno[3,2,e]1,2 thiazene-6 sulfonamide-1,1 dioxide) is a carbonic anhydrase inhibitor disclosed in U.S. Pat. No. 5,378,703 and sold in a topical ophthalmic formulation (Azopt.TM.) for lowering elevated intra-ocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT) (Alcon Laboratories, Inc., Fort Worth, Tex.).
Brimonidine tartrate ((5-bromo-6-2-imidzolidisnylideneamino) quinozoline L-tartrate) hereinafter "brimonidine" is a relatively selective alpha-2-adrenergic agonist sold in a topical ophthalmic formulation (Alphagan.TM.) for lowering elevated IOP in patients with open angle-glaucoma or ocular hyp e r tension (Allergan, Inc., Irvine, Calif.).
U.S. Pat. No. 3,890,319 discloses a class of compounds, including brimonidine, and their usefulness as antihypertensive agents. Certain co mpounds in the group have also been disclosed for treating physical pain, anaesthetizing~ the central nervous system, to constrict blood vessels, treat ischemia, decongest nasal passages, effect reduction of one or more effects of an inflammatory disorder to increase retinal blood flow, and effect an altration in the rate of fluid transport in the gastrointestinal tract, see U.S. Pat. No. 5,756,503 (Column 1, lines 16-22). WO 97/01339 discloses the use of brimonidine to protect the optic nerve and the retina from "noxious provocations," see page 1, first paragraph.
Oral and i.v. administration of the CAIs, acetazolamide and methazolamide, are known to increase both ocular and cerebral blood flow. The dosages used to achieve meaningful results are relatively high and is due to a number of factors. These compounds have relatively low affinity for carbonic anhydrase in as measured by their Ki (disassociation constant) values and are only modest inhibitors of the enzyme as measured by their IC.sub.50 values. They have low distribution coefficients (octanol/water determined at pH 7.4) which is a measure of their lipophilicity. This low lipophilicity limits their ability to cross the blood retinal barrier. Finally, these compounds have relatively short half-lives in whole blood. This relatively rapid elimination rate limits their ability to redistribute into the back of the eye and maintain adequate drug concentrations.
The preclinical and clinical data for the effect of topically dosed CAIs, in particular dorzolamide, on ocular blood flow are conflicting. Gruenwald, et al., Acta Ophthalmologica, 75:236-238 (1997) disclosed that the use of dorzolamide has no effect on retinal vein blood flow in normal volunteers. Pillunat, et al., ARVO abstract, Investigative Ophthalmology & Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) showed that topical dorzolamide did not alter optic nerve head blood flow in healthy subjects. Shipman, et al., ARVO abstract, Investigative Ophthalmology & Visual Sciences, Vol. 38, No. 4 (Mar. 15, 1997) found that dorzolamide did not alter the choroidal pressure flow relationships. Koller, et al., ARVO abstract, Investigative Ophthalmology & Visual Sciences, Vol. 38, No.4 (Mar. 15, 1997) showed that topical dorzolamide did not change peripapillary blood flow. A study by Harris, et al., Acta Ophthalmologica, 74:4896 (1996) said dorzolamide accelerated blood velocity in the retina and superficial optic nerve head; and another study by Sugrue, et al. J. Ocular Pharm., 12 (3) 363-376 (1996) teaches that topical dorzolamide does not decrease blood flow to the iris, ciliary processes, optic nerve, or retina in rabbits. Sponsel has presented a few studies which suggest that topical dorzolamide has a positive effect on ocular blood flow. See ARVO abstracts, Investigative Ophthalmology & Visual Sciences, Vol. 37, No. 3 (Feb. 15, 1996) and Vol. 38, No. 4 (Mar. 15, 1997). Healthy subjects treated with dorzolamide exhibited accelerated artereovenous passage time and an increase in optic nerve head velocity is described in WO 96/37203. The publication further discloses the use of topical carbonic anhydrase inhibitors (CAIs) to increase retinal and optic nerve head blood velocity. Brinzolamide is not disclosed in any of these references.